The Combination of MEK and BRAF Inhibitor Drugs Within Papillary Thyroid Cancer
Within Papillary Thyroid Cancer, the BRAF V600E gene gets mutated, which is one of the most major mutations within this specific type of cancer. The BRAF gene is frequently mutated in papillary thyroid cancer with V600E mutation resulting in rapid tumor growth and lower overall survival. Initially a treatment option is by experimenting with an BRAF inhibitor drug to slow the rapid growth of the tumor. A study driven by Dr. Liang Cheng, shows how various BRAF and MEK inhibitor drugs were used to create a combination for suppressing the tumor. However, in this case, this experiment was targeted towards melanoma. In other instances, a MEK inhibitor drug targets the MAP kinase and potentially stops the growth of the tumor, which when the MEK is inhibited, then cell proliferation is stopped, therefore allowing apoptosis to occur. This experiment lays out a detailed plan to combine the two drugs together to see if the combination will expedite the hinderance of the BRAF gene mutation. The drugs are designed to turn off signaling pathways that are activated downstream of the mutation. The MEK inhibitor drug that will be tested is the trametinib drug, and the BRAF inhibitor drug used is the dabrafenib drug, In most cases the MEK drugs are given solely to the patients or they only get the BRAF inhibitors but together, they could help to slow the process of the BRAF gene mutations and block the growth of the tumor. This leads me to my research question: “How can we expedite the process of the MEK and BRAF inhibitors in the hinderance of the BRAF mutation for Papillary Thyroid Cancer?”
Background:
The BRAF V600 gene mutation is fairly common within patients that have papillary thyroid cancer, and is less common in children. Cancers that have the BRAF mutation tend to grow quickly and spread to other parts of the body. The BRAF mutation changes make the cells grow and divide uncontrollably. Typically, a BRAF genetic test looks for the mutations in the BRAF gene. Once a patient is determined to have the mutation, it doesn’t necessarily mean that the patient has cancer, yet it does indicate a much higher risk of obtaining cancer in the future. Common treatment includes targeted drug therapies. The MEK gene works close with the BRAF gene so that the drugs can block the MEK proteins and help treat the cancers with BRAF genetic mutations. Figure 1 below, demonstrates the molecular pathway of the BRAF mutation in tumor growth. Typically, either a MEK inhibitor or a BRAF inhibitor is used for the targeted drug therapy, however, they have not been used in conjunction with one another for thyroid cancer, only for melanoma.
Significance:
This experiment aims to bridge the gap in the inhibitor testing and be able to start testing the effect of combining two drugs on thyroid cancer. In the past, almost all experiments and research studies have been shown to only be tested on patients with melanoma and lung cancer, however a vast portion of patients with the BRAF mutation end up having papillary thyroid cancer. This would represent a new therapy for patients struggling with thyroid cancer.
Specific Aim:
A MEK inhibitor is a chemical and drug that inhibits the MAP kinase and can potentially stop the initiation of the growth of the tumor. By experimenting on the MEK inhibitor, it targets the MAP kinase regarding the thyroid cancer, which when targeted, will slow down the progression of the cell growth. When the MEK is inhibited, cell proliferation is blocked, and therefore apoptosis can happen and is induced.
This brings us to the hypothesis; by combining the MEK inhibitor with a BRAF inhibitor, it will expedite the hinderance of the BRAF genetic mutation in relation to Papillary Thyroid Cancer. The null hypothesis is that by combining the MEK inhibitor with a BRAF inhibitor, it will not expedite the hinderance of the BRAF genetic mutation in relation to Papillary Thyroid Cancer.
Specifically, this experiment will determine if mixing the MEK inhibitor drug with the BRAF inhibitor drug will expedite the hinderance of the BRAF genetic mutation and will shrink the tumors for longer periods of time. The MEK inhibitor drugs that will be tested Is the trametinib drug which helps lower the risk of cancer coming back. Trametinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells. Dabrafenib is the drug that will be used for the BRAF inhibitor drug.
Research Strategy:
In most cases, the MEK drugs are solely given to the patients, or they only get the BRAF inhibitors, but together, they could help to show the process of the BRAF gene mutations and block the growth of a tumor. Previous other studies have shown that the combination of Trametinib and Dabrafenib have been given out to patients in various dosages and ratios (Atkins). For example, some studies have given out the combination therapy with equal parts of each drug, while others have given it out with a 30:70 split. The two drugs picked are crucial because they have been used before for non-small cell lung cancer and melanoma, so by putting them to test with thyroid cancer it allows us to see if it will help the BRAF mutations specifically for patients with thyroid cancer.
The experimental groups being used first would be regular cell lines without any drugs added to them, and this would be the negative control. Then there would be one group that has just the Trametinib, another group that has just the Dabrafenib, and then a fourth group with both mixed together to see how each variable works alone and to see if there will be a significant difference when the drugs are mixed together.
With both the positive and negative controls in this experiment this is what is expected as the outcome. For the positive control it is: by mixing the MEK and BRAF inhibitor drugs together, it will show that together they will help slow down the process resulting from the BRAF genetic mutation which will show zero/minimal growth of a tumor. And for the negative control it is: by only administrating the BRAF inhibitor drugs, it will show the response time of the drugs and that it takes longer for one drug to work on the genetic mutation.
This leads us to our potential observations and interpretations of them. The first potential observation is that the experimental control groups will have slower growth rates of tumor. This can happen due to the mixing of the drugs together; it correlates with the probability of minimizing the tumor growth. The second potential observation is that the experimental group will not have any significant change, and the tumor will grow at similar rates. This is due to the fact that drug mixing does not depend or correlate with the rate at which the tumor grows. Lastly, the final observation could be that nothing happens in terms of the tumor growth with the experimental group, which could be due to the drugs mixing together does not inhibit the tumor growth.
Pitfalls/Alternative Strategies:
The first pitfall is as follows: because we are mixing two drugs together, there may be more health risks of the combination of the drugs. However, the alternative approach that can be taken is to try switching up the percentages of the drug mixture (ex. 30% BRAF inhibitor drug, 70% MEK inhibitor drug). To measure the success of this, the cell lines would be held under the same time frame as the original experiment, however, instead the two lines would be compared to see which one had a more positive impact on the cells in terms of reducing the tumor growth. The second pitfall is that the drug mixture only lasts a couple of days. The alternative approach to this would be to adjust the amount of dosage every couple of months to maximize the longevity of the combination therapy.
Future Directions:
In the future, other experiments could test if different percentages of the mixtures of the inhibitor drugs will expedite the hindrance of the BRAF mutation. This means that we should test different ratios of the drug combinations to test the proportions of the drugs to see the difference of the outcomes. Another way to take the findings of this experiment would be to use the mixture of the drugs found to target multiple other genetic mutations within papillary thyroid cancer. This can be achieved by mixing combinations of different other drugs as well, such as Cobimetinib and Binimetinib.
Throughout the process of the experiment, the purpose is to see if mixing a combination of the drugs will help to increase the rate at which the BRAF mutation is suppressed in thyroid cancer. With just the BRAF inhibitor and MEK inhibitor drugs, it can take years to see any progress, so the hope by mixing the drugs is so that it can expedite the process and help more patients. These drugs should work together by shrinking the tumor and preventing it from ever coming back again.
